A Novel Role of Interleukin-13 Receptor α2 in Pancreatic Cancer Invasion and Metastasis

Toshio Fujisawa,Bharat Joshi,Atsushi Nakajima,Raj K Puri

doi:10.1158/0008-5472.can-09-2100

Abstract

Whereas interleukin-13 receptor alpha2 chain (IL-13Ralpha2) is overexpressed in a variety of human solid cancers including pancreatic cancer, we investigated its significance in cancer invasion and metastasis. We used two pancreatic cancer cell lines, IL-13Ralpha2-negative HPAF-II and IL-13Ralpha2-positive HS766T, and generated IL-13Ralpha2 stably transfected HPAF-II as well as IL-13Ralpha2 RNA interference knocked-down HS766T cells. Ability of invasion and signal transduction was compared between IL-13Ralpha2-negative and IL-13Ralpha2-positive cells and tumor metastasis was assessed in murine model for human pancreatic cancer with orthotopic implantation of tumors. IL-13 treatment enhanced cell invasion in IL-13Ralpha2-positive cancer cell lines but not in IL-13Ralpha2-negative cell lines. Furthermore, gene transfer of IL-13Ralpha2 in negative cell lines enhanced invasion, whereas its silencing downmodulated invasion of pancreatic cell lines in a Matrigel invasion assay. In vivo study revealed that IL-13Ralpha2-positive cancer metastasized to lymph nodes, liver, and peritoneum at a significantly higher rate compared with IL-13Ralpha2-negative tumors. The expression of IL-13Ralpha2 in metastatic lesions was found to be increased compared with primary tumors, and mice with IL-13Ralpha2-positive cancer displayed cachexia and poor prognosis. Invasion and metastasis also correlated with increased matrix metalloproteinase protease activity in these cells. Mechanistically, IL-13 activated extracellular signal-regulated kinase 1/2 and activator protein-1 nuclear factors in IL-13Ralpha2-positive pancreatic cancer cell lines but not in IL-13Ralpha2-negative cell lines. Taken together, our results show for the first time that IL-13 can signal through IL-13Ralpha2 in pancreatic cancer cells and IL-13Ralpha2 may serve as a prognostic biomarker of invasion and metastasis in pancreatic cancer.

Highlights

The natural history of pancreatic cancer is characterized by local invasion of adjacent structures and early metastasis to lymph nodes and liver [1, 2]
Our results unequivocally show a novel role of IL-13Rα2 in pancreatic cancer invasion and metastasis and that IL-13Rα2 is directly involved in signaling through the AP-1 pathway
We studied two pancreatic cancer cell lines to examine the effect of IL-13 on cancer invasion and metastasis

Summary

Introduction

The natural history of pancreatic cancer is characterized by local invasion of adjacent structures and early metastasis to lymph nodes and liver [1, 2]. By the time of diagnosis, most pancreatic cancers are advanced and unresectable; at present, very little effective therapy can be offered to these patients. A bispecific cytotoxin targeting receptors for epidermal growth factor and human IL-13 is shown to be effective in animal model of pancreatic cancer [13]. IL-13Rα1 is a low-affinity IL-13R, but after binding to IL-13, it recruits IL-4Rα and forms a high-affinity IL-13R complex (type II IL-13R) and mediates signal transduction through the JAK-STAT6 pathway [15]. It has been reported that IL-13 can signal through IL-13Rα2 in murine macrophage cell line and that its signaling is STAT6-independent and involves the AP-1 pathway to induce activation of transforming growth factor-β1 activity [19]

Methods

Results

Conclusion